Women's Health Initiative’s landmark hormone replacement research 10 years after

Seminal study found significantly higher risk of heart disease, stroke, breast cancer from combined hormone replacement therapy; as a result, 15,000-20,000 fewer breast cancer cases each year
Fred Hutchinson Cancer Research Center's Dr. Andrea LaCroix is a Women's Health Initiative investigator. Center News file photo

Ten years ago, millions of American women woke up to news that would have a profound effect on decisions about their health. The Women's Health Initiative had released findings that combination hormone replacement therapy—at the time prescribed to 15 million postmenopausal women in the U.S. to alleviate symptoms of menopause and to prevent fractures and heart attacks—significantly increased the risk of heart disease, stroke and breast cancer.

'Revolutionary set of findings'

July marks the 10th anniversary of the WHI's first publication describing the risks of combination hormone therapy. That paper, published in the Journal of the American Medical Association, has singularly changed the face of women's medicine around the world. Researchers estimate that because of the decrease in hormone therapy use following the WHI publication, there have been 15,000-20,000 fewer cases of breast cancer each year in the United States.

"It was a revolutionary set of findings that came out in that paper," said Dr. Andrea LaCroix, of the Public Health Sciences Division and a WHI investigator. "That was a watershed moment after which many things changed with respect to hormone therapy and disease. Since then, women's use of hormone therapy has plunged in the U.S. and many other countries, and this has been followed by measurable decreases in breast cancer in several countries and, in the U.S., decreases in heart attack and stroke."

Center played leading role

The Hutchinson Center played a leading role in that groundbreaking event. The WHI's Clinical Coordinating Center is housed at the Center and many Center faculty are WHI investigators. Seattle is home to one of the WHI's 40 clinical sites, coordinated jointly by the Center and University of Washington.

The WHI's hormone therapy trials were initiated in 1993 to test, as past studies had suggested, whether long-term use of hormone therapy could prevent heart disease, hip fractures and other diseases.

More than 27,000 women from around the country, including more than 700 from the Seattle area, volunteered for two trials of medications that many took for granted as beneficial for relieving hot flashes and other menopausal symptoms: one that tested combination hormone therapy, estrogen plus progestin, in postmenopausal women, and one that tested estrogen alone in women who had had a hysterectomy. (Estrogen alone is not prescribed for women with an intact uterus as it can cause endometrial cancer, cancer of the uterine lining).

When the WHI trials started, there were many reports from observational studies that these treatments could also prevent heart disease. So the WHI's 2002 finding that estrogen plus progestin actually increased the risk of heart attacks and stroke, in addition to increasing the risk of breast cancer, came as a shock to the medical community and public. The estrogen plus progestin trial was halted three years earlier than planned because the data were so clear.

Empowering women to make decisions

"The 2002 paper was dramatic in many ways," said Dr. Garnet Anderson of the Public Health Sciences Division. "It had this immediate public health impact, because women could make the decision to change their lifestyle on their own. They could just decide, I'm not going to take these risks, I'm going to stop taking these pills today. It was also a dramatic research finding because it contradicted a lot of the preliminary work that motivated that trial."

In 2004, the WHI also halted its estrogen-alone trial early. Although estrogen alone does not carry the same dramatic health risks as combination therapy, it did increase the risk of stroke and did not protect against heart disease in women over 60. Later follow-up studies by WHI researchers showed that estrogen therapy actually protects against some types of breast cancer, a finding that still mystifies the research community given that many studies had suggested that breast cancer risk increases with long-term estrogen use.

In the past decade, many follow-up studies and news stories have been published about the relationship between hormone therapies and diseases. With all this information, women can often be confused about what treatment is right for them.

"There are subtleties in the effects of hormone therapy, but the basic story that we gave for estrogen plus progestin in 2002 hasn't changed," Anderson said. "The adverse effects are so clear that it shouldn't be used for prevention. Even for women suffering from menopausal symptoms, the lowest dose and shortest time possible has to be the recommendation."

"Our experience with the hormone therapy trials reinforces the need for occasional large-scale disease prevention trials, in spite of their cost and logistical complexity, when the public health implications are sufficiently important," said Dr. Ross Prentice, director of the Public Health Sciences Division and WHI investigator.

Hormone replacement therapy primer

WHI investigated the effects of two common types of hormone therapy on risks of various diseases in women. Estrogen plus progestin therapy is prescribed to postmenopausal women; estrogen alone is used in women who have had a hysterectomy. For more information, visit http://whi.org/.

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